Written by Miyako Rogers, Science Writer
A new genomic study of lymphocytes published in Nature has revealed that mutations occurring during normal physiological processes may be implicated in cancer development. This study also shows that in lymphocytes, mutations accumulate at a constant rate, suggesting they may be regulated by an internal clock and are involved in the process of ageing.
New clonal expansion protocol
Researchers performed whole-genome sequencing of over 700 lymphocytes from individuals aged 0-81. They then investigated how and when cells accumulated mutations and how the mutational profile varied between different cells and individuals. To achieve this, researchers developed a new method for in vitro clonal expansion. This allowed researchers to grow colonies of over 30 lymphocytes from a single cell.
Turning into cancer
B-cell and T-cell lymphocytes constantly undergo a certain amount of genetic mutations to generate antigen-receptor diversity. These genetic mutations are supposed to be confined to antibodies and antigen receptors. However, researchers found that a significant amount of collateral damage occurs elsewhere in the genome during this process. These off-target mutations in healthy B-cells were very similar to those in lymphoma, suggesting that this process alone may be sufficient to cause lymphoid malignancy. This study also found a higher variation in mutations cell to cell than individual to individual. Altogether, this suggests that mutational changes within cells are more likely to cause cancer than inherited mutations in the genome.
The ageing process
Researchers also found that changes in the number of mutations in each cell were primarily influenced by age. The burden of single-nucleotide variants (SNVs) increased linearly with age across all cell types. Naïve B cells accumulated approximately 15 SNVs per year, and memory B cells accumulated 17 SNVs per year. T-cells had higher mutation rates, with naïve T-cells accumulating 22 SNVs per year and memory T-cells accumulating 25 SNVs per year. The burden of known endogenous mutational signatures were also found to correlate linearly with age. Overall, these findings suggest that there may be an internal clock-like process that causes mutations to occur at a specific and constant rate for each cell type.
Implications and future directions
This study is the first to characterize the mutational profiles of healthy lymphocytes in this much detail, and the results suggest that environmental forces may have a greater influence on cancer development than inherited risk factors. These findings challenge the current trend toward genetic screening and testing in cancer prevention strategies and treatments. This study also sheds light on the role of mutations in the ageing process and helps to build a better picture of the link between the immune system and ageing. Furthermore, the new method of clonal expansion outlined in this study could be very useful for future in vitro research.